More than 80% of patients with refractory diffuse large B-cell lymphoma (DLBCL) respond to CD19- targeting chimeric antigen receptor (CAR) T cell therapy. Yet, 50% of these patients will relapse. CD19 antigen loss is a common mechanism for CD19-CAR therapy failure in B-cell acute lymphoblastic leukemia (B- ALL), and similar data is now emerging for DLBCL patients. CD22 is a B-cell malignancy associated antigen and a small Phase I trial of CD22-CAR therapy has shown promise in B-ALL even in those patients who failed CD19-CAR therapy. Interesting, CD22 antigen escape was also seen in these B-ALL patients. In preclinical models, high antigen density was associated with optimal CAR T cell response, however the role of antigen density's impact on clinical response has not been fully investigated. This CD22-CAR therapy has yet to be evaluated in refractory DLBCL patients and the role of CD22 antigen density's impact on response and relapse is unknown. Based on these observations, Dr. Frank, an Instructor in the Division of Blood and Marrow Transplantation at Stanford University, has proposed in his K08 application to investigate novel CAR therapies in DLBCL patients while undergoing an intensive training program to prepare him to launch an independent translational research program. Dr. Frank's training plan focuses on developing additional skills in clinical trial design and management; and in gaining advanced expertise in immunology and bioinformatic methods. This training will nicely harmonize with his three research aims. He proposes to conduct a Phase I trial investigating the safety and efficacy of this CD22-CAR therapy in patients with refractory DLBCL. Second, he wishes to determine whether surface antigen density impacts clinical response and relapse for patients receiving CD22- CAR therapy and whether antigen evasion can be mitigated by a bispecific CD19/CD22-CAR therapy, currently being investigated in DLBCL patients. Third, he desires to investigate how CAR T therapy influences circulating tumor DNA (ctDNA) dynamics in patients undergoing CD22-CAR and CD19/CD22-CAR therapy to optimize post-treatment surveillance strategies. As part of this third aim, he proposes to use a Stanford- developed ctDNA technology, CAPP-Seq, to identify mutations associated with CAR therapy resistance. To oversee Dr. Frank's training and research, he will be mentored by Drs. Crystal Mackall and David Miklos, leading experts in CAR T cell therapy. In addition, Dr. Frank has recruited Dr. Ronald Levy, a world-renowned leader in lymphoma and immune-based therapies, and Dr. Ash Alizadeh, a leading expert in ctDNA technologies, to serve as advisors and potential collaborators in his training and in accomplishing his aims. In carrying out his proposed research and training plan under the guidance of outstanding mentorship, Dr. Frank will be equipped to compete for R01 level of funding, publish high-level papers, and to launch an independent career leading a translational research program.